tbuckley/cabot-search huggingface dataset:
Abstract 5278: Cancer WHIRI research: Improving the early cancer pathway for indigenous NZ peoples
Authors: Nina Scott, Myra Ruka, Amy R. Jones
Journal: Cancer Research (2022)

Abstract Background: Māori, Indigenous peoples of New Zealand (NZ) are twice as likely to die after a diagnosis of cancer compared to non-Māori. Cancer pathways are not designed for Māori health gain and are not pandemic resilient. Māori receive delayed poorer quality treatment and those with comorbidities are undertreated [1]. Existing inequities from time of referral to cancer services through to treatment were exacerbated by the COVID-19 response in Aotearoa NZ. Coordination of care is crucial for Māori patients and whānau (family), but poorly developed along this early part of the cancer pathway. In addition, care quality is not well monitored, and the current pathway is vulnerable to changes created by pandemic conditions. Aims: This study seeks to co-design, implement and evaluate a holistic cultural and clinical cancer service that is patient and whānau centred; the Whānau Hauora Integrated Response Initiative (WHIRI) programme. This comprehensive, pandemic resilient, racism-free, hauora (wellbeing) enhancing and responsive model of care will be designed for the early part of the secondary care cancer pathway. Design and Method: The WHIRI programme includes navigation, a holistic whānau/family hauora assessment tool, proactive management by a team of clinicians and a team responsible for making systems changes. WHIRI was launched mid-pandemic (early 2020) for kaumātua (elderly Māori) with long-term conditions and ran for 3 months. During COVID we found that WHIRI had the potential to change hospital systems and improve experiences for patients and whānau. WHIRI ensures the provision of best-practice timely treatment for Māori patients and could make large gains in closing the survival gap between Māori and non-Māori in the short- to medium-term, leading to reductions in Māori cancer deaths. We plan to redesign WHIRI into a cancer programme that functions effectively in all COVID levels using qualitative Kaupapa Māori methodology. Key to this methodology is partnerships with patients, whānau, cancer clinicians, Māori navigators and The Cancer Control Agency New Zealand. We will present our methods and co-design model of cancer care. We will outline the potential to expand the model nationally with reach from primary care all the way through to palliative care. It will also provide a platform for future research to measure the impact of WHIRI on cancer and whānau care. 1. Hill S, Sarfati D, Blakely T, Robson B, Purdie G, Chen J, et al. Survival disparities in Indigenous and non-Indigenous New Zealanders with colon cancer: the role of patient comorbidity, treatment and health service Citation Format: Nina Scott, Myra Ruka, Amy R. Jones. Cancer WHIRI research: Improving the early cancer pathway for indigenous NZ peoples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5278.
Abstract 5532: An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy
Authors: Minh D. To, Manjunatha Ankathatti Munegowda, Rosemina Merchant, Aanchal Sharma
Journal: Cancer Research (2022)

Abstract Introduction: Combination studies with engineered IL-2 variants and immune-checkpoint blockade have demonstrated synergy in both pre-clinical models and the clinic. Co-administration of those 2 agents can potentially face challenges related to overlapping toxicities in obtaining optimal doses for synergistic effects. We propose to potentiate the synergy by enabling cis activation of IL-2 agonism and blockade of PD-1/PDL-2 binding with a single anti-PD1-IL2 to generate Bifunctional SuperKines for ImmunoTherapy (BiSKIT). Both human (h) and mouse (m) versions of anti-PD1 are fused with MDNA109FEAA, an IL-2 superkine with enhanced affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). Experimental Procedure: Studies included binding analyses with Biacore/SPR, signaling analyses in an IL-2 cell reporter assay, cell proliferation assay, in vitro pSTAT5 signaling in human PBMCs, PD1/PDL-1 cell reporter assay and efficacy in syngeneic tumor models. Summary of Data: Anti-hPD1-MDNA109FEAA and surrogate anti-mPD1-MDNA109FEAA were tested in both in vitro and in vivo assays. Both constructs demonstrated selective binding to either hPD1 or mPD1 as expected, and the MDNA109FEAA motif retained its receptor selectivity (enhanced affinity to CD122 and no binding to CD25). In both HEK-Blue IL-2 reporter and CTLL-2 proliferation bioassays, anti-PD1-MDNA109FEAA exhibited similar agonistic effect as MDNA109FEAA-Fc, demonstrating that potency towards the IL-2 axis was not diminished. This was further confirmed with pSTAT5 signaling in primary human PBMCs where anti-PD1-MDNA109FEAA showed enhanced activation of CD8 T-cells and NK cells with reduced activity on Treg when compared to rhIL-2. Both constructs were also effective at inhibiting PD1/PDL-1 pathway in respective human and mouse specific cell-based reporter assays. In a CT26 syngeneic colon tumor model, anti-mPD1-MDNA109FEAA exhibited superior efficacy over monotherapy and combination with anti-mPD1 and MDNA109FEAA-Fc when administered at equal molar dosage and same schedule. Conclusion: We have engineered anti-PD1-MDNA109FEAA to enable cis engagement with IL-2 receptor and PD1 as an approach to activate immune cells while reducing their exhaustion. Anti-mPD1-MDNA109FEAA achieved potent efficacy in a CT26 colon tumor model and is currently being evaluated in additional syngeneic tumor models with varying responsiveness to immune checkpoint blockade. Citation Format: Minh D. To, Manjunatha Ankathatti Munegowda, Rosemina Merchant, Aanchal Sharma. An ‘anti-PD1-IL2 beta-only super-agonist’ displays potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5532.
Abstract 5941: A simulation modeling study to support personalized breast cancer prevention and early detection in high-risk women
Authors: Jinani Jayasekera, Amy Zhao
Journal: Cancer Research (2022)

Abstract Purpose: To evaluate the impact of early detection with screening and primary prevention with risk-reducing medication to provide personalized data that will help identify women who are more likely to benefit from various interventions or combinations of interventions with the least harms. Methods: We adapted the CISNET microsimulation model G-E of breast cancer natural history to evaluate the harms and benefits of annual mammography and risk reducing medication among high-risk women (i.e., 5-year risk greater than or equal to 3%). Model G-E is a discrete event microsimulation model that follows millions of women from birth to death and captures the variability in distributions of each event. Each simulated woman is assigned a cohort-specific life expectancy which is used to select a date of breast cancer death. For this study, we dynamically updated the risk of developing breast cancer for each simulated woman based on her family history, breast density, age and history of biopsy. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, incidence and stage without screening, other cause mortality by age, screening performance (sensitivity/specificity), survival by age, stage, and subtype without treatment, treatment efficacy, and other cause mortality. We compared model outcomes for screening alone vs. screening with a 5-year course of risk reducing medication. We modeled various screening strategies including annual or biennial screening starting at ages 35, 40, 45 and stopping at ages 65 and 74 years. Model outcomes for each strategy included, the benefits of risk-reducing drugs (avoiding breast cancer) and screening (breast cancer stage, breast cancer-specific survival), and harms of screening (false positives, overdiagnosis). We also conducted sensitivity analysis to estimate the effects of uncertainty in model inputs or assumptions on results. Results: We found that risk reducing medication could result in an additional 28% decrease in invasive breast cancer incidence, 20% decrease in stage IV diagnosis, and a 30% decrease in breast cancer death if screening started at age 35 in a high-risk woman. However, potential breast density changes due to risk reducing medication among high-risk women could result in a 19% increase in false positive screening results compared to screening alone. The results varied by the starting age of screening. Conclusions: Simulation modeling is useful in assessing the relative benefits and harms of screening and risk reducing medication in high-risk women. Citation Format: Jinani Jayasekera, Amy Zhao. A simulation modeling study to support personalized breast cancer prevention and early detection in high-risk women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5941.
Abstract 2231: Surface-enhanced Raman scattering paltform of nanometal for exosome analysis in hepato-cellular carcinoma
Authors: Ola Sayed Ahmed, hisham imam, abdel Rahman zekri
Journal: Cancer Research (2022)

Abstract Exosomes could be a source of cancer biomarkers in the future. Exosomes derived from tumors could provide a non-invasive way to diagnose cancer, assess cancer progression, and track treatment responses. However, exosome analysis would be aided by new molecular methods, which would speed up basic and clinical exosome research. Exosome research is rapidly advancing, providing new insights into the physiological role of exosomes and their significant link to human health. Although tumor-derived exosomes have been shown to be promising biomarkers for cancer detection and disease progression due to their inherited biological contents from the parent cancer cells and unique roles in tumor metastasis and invasion, rapid and effective isolation from complex biological samples and high-precision real-time analysis remains a difficult task. In this work, we present a surface-enhanced Raman scattering (SERS) platform for integrating multiple hepatocellular carcinoma exosomes conventional method to read different peak positions and amplitudes of spectrum, whole SERS spectra of exosomes were analyzed by principal component analysis (PCA). In addition, label-free analysis of purified exosomes from normal cell and hepatocellular carcinoma were clearly distinguished from normal cell derived exosomes by 96.4% sensitivity and 98.2% specificity using surface-enhanced Raman spectroscopy (SERS). In this study, the possibility of using exosomes as biomarkers for the detection of hepatocellular carcinoma (HCC) was discussed. From this study, SERS can serve as a valuable tool for separating exogenous subpopulations and can be used to characterize exosomes for cancer diagnosis. Citation Format: Ola Sayed Ahmed, hisham imam, abdel Rahman zekri. Surface-enhanced Raman scattering paltform of nanometal for exosome analysis in hepato-cellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2231.
Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune-modifying therapies: a nationwide cohort study in the OpenSAFELY platform
Authors: Brian MacKenna, Nicholas A Kennedy, Amir Mehrkar, Anna Rowan, James Galloway, Julian Matthewman, Kathryn E Mansfield, Katie Bechman, Mark Yates, Jeremy Brown, Anna Schultze, Sam Norton, Alex J Walker, Caroline E Morton, David Harrison, Krishnan Bhaskaran, Christopher T Rentsch, Elizabeth Williamson, Richard Croker, Seb Bacon, George Hickman, Tom Ward, Simon Davy, Amelia Green, Louis Fisher, William Hulme, Chris Bates, Helen J Curtis, John Tazare, Rosalind M Eggo, David Evans, Peter Inglesby, Jonathan Cockburn, Helen I McDonald, Laurie A Tomlinson, Rohini Mathur, Angel Y S Wong, Harriet Forbes, John Parry, Frank Hester, Sam Harper, Ian J Douglas, Liam Smeeth, Charlie W Lees, Stephen J W Evans, Ben Goldacre, Catherine H Smith, Sinéad M Langan
Journal: The Lancet Rheumatology (2022)

The risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases and on immune-modifying drugs might not be fully mediated by comorbidities and might vary by factors such as ethnicity. We aimed to assess the risk of severe COVID-19 in adults with immune-mediated inflammatory diseases and in those on immune-modifying therapies.
Trends in De Novo Hypertensive Disorders of Pregnancy Among Asian and Hispanic Population Subgroups in the United States, 2011 to 2019
Authors: Nilay S. Shah, Katharine A. Harrington, Xiaoning Huang, Natalie A. Cameron, Lynn M. Yee, Sadiya S. Khan
Journal: JAMA Cardiology (2022)

De novo hypertensive disorders of pregnancy (HDP) are associated with adverse maternal and offspring outcomes. Heterogeneity among racial and ethnic subgroups may be masked with aggregate reporting of race and ethnicity, such as Asian or Pacific Islander or Hispanic.To determine patterns in de novo HDP rates among individuals in Asian and Hispanic subgroups with a first live birth in the United States in the period 2011 through 2019.This serial cross-sectional analysis used data from 2011 through 2019 for individuals aged 15 to 44 years with singleton first live births obtained from the US National Center for Health Statistics natality database.Stratification by self-report of maternal race and ethnicity: Hispanic/Latina (overall and Hispanic/Latina subgroups [Central/South American, Cuban, Mexican, and Puerto Rican]), non-Hispanic Asian and Pacific Islander (overall and non-Hispanic Asian subgroups [Asian Indian, Chinese, Filipina, Japanese, Korean, and Vietnamese]), non-Hispanic Black, non-Hispanic White.De novo HDP was defined as new-onset hypertension during pregnancy (gestational hypertension or preeclampsia). Age-standardized rates of HDP (per 1000 live births) and respective mean annual percent change in race and ethnicity groups and subgroups were calculated.Among 13 238 918 individuals, the mean (SD) age was 26.3 (5.8) years. Overall, HDP rates increased 7.3% per year (95% CI, 6.5%-8.1%), from 57.2 (95% CI, 56.8-57.6) per 1000 live births in 2011 to 99.7 (95% CI, 99.2-100.2) per 1000 live births in 2019. Rates of HDP significantly increased in all racial and ethnic groups and subgroups over the study period. The highest HDP prevalence among non-Hispanic Asian subgroups in 2019 was in Filipina individuals (92.5 [95% CI, 86.3-98.8] per 1000 live births), and the highest among Hispanic/Latina subgroups in 2019 was in Puerto Rican individuals (98.6 [95% CI, 94.2-102.9] per 1000 live births) with significant heterogeneity observed among subgroups across the study period.Rates of HDP among individuals with a singleton first live birth increased in the United States from 2011 to 2019 across all race and ethnicity subgroups, with considerable heterogeneity in HDP rates in non-Hispanic Asian and Hispanic/Latina subgroups.
Abstract 1370: Targeting LSD1 rescues MHC-I antigen presentation in small cell lung cancer
Authors: Minh N. Nguyen, Hirokazu Taniguchi, Andrew Chow, Yingqian A. Zhan, Triparna Sen, Charles M. Rudin
Journal: Cancer Research (2022)

Abstract Purpose: Small cell lung cancer (SCLC) is a highly aggressive cancer with early primary resistance and modest clinical benefit to immune checkpoint blockade (ICB). Mutation or transcriptional repression of the major histocompatibility complex class I (MHC-I) is a key mechanism driving resistance to T cell-based therapies. Lysine Demethylase 1 (LSD1) regulates gene expression through modulating mono- and di- methylated lysine 4 and 9 of histone H3. LSD1 is a therapeutic target of interests in SCLC due to its oncogenic requirement for tumor growth, and there has been growing evidence pointing to LSD1 as a repressor of tumor-intrinsic immunogenicity. Here investigated the role of LSD1 as a transcriptional regulator of antigen presentation in SCLC. Method: To perturb LSD1 function, we employed the pharmacological inhibitor ORY-1001 and shRNA-mediated knockdown. We then assessed changes in MHC-I expression on SCLC cell lines by flow cytometry and western blot. To analyze transcriptional changes following LSD1 inhibition, we performed RNA-seq on SCLC cells pre- and post-treatment with ORY-1001. To observe for antigen-specific T cell killing, we engineered SCLC cells to express endogenous antigens and co-cultured these cells with primary cognate CD8+ T cells. Finally, we treated genetically engineered mouse model (GEMM)-derived tumors on immunocompetent syngeneic mice with ORY-1001 with or without anti-PD-L1 blockade to assess for anti-tumor effects. Results: We discovered a significant and strong negative correlation between expression of LSD1 and genes encoding the MHC-I antigen presentation pathway. Inhibition of LSD1 induces expression of MHC-I genes and restores expression of genes encoding the antigen presentation machinery. Perturbation of LSD1 further activates interferon signaling and interferon-inducible expression of NLRC5, a well-characterized transcriptional activator of MHC-I genes. We further showed that targeting LSD1 sensitizes SCLC cells to MHC-I-restricted T cell-dependent cytolysis and enhances ICB efficacy in refractory SCLC tumors. Conclusion: Our data define a role for LSD1 as a potent negative regulator of MHC-I-mediated antigen presentation and provide rationale for the use of LSD1 inhibitors to augment response to immunotherapy in SCLC. Citation Format: Minh N. Nguyen, Hirokazu Taniguchi, Andrew Chow, Yingqian A. Zhan, Triparna Sen, Charles M. Rudin. Targeting LSD1 rescues MHC-I antigen presentation in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1370.
Abstract 5463: BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers
Authors: Ling Li, Bang Fu, Han Han, Zhongxin Sun, Xiangdong Zhao, Xuepeng Jv, Jun Tong, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Wei Ren, Yinlong Li, Wenmao Wu, Jing Guo, Dan Yan, Xiangyong Liu, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang
Journal: Cancer Research (2022)

Abstract Src homology region 2 domain-containing phosphatase-2 (SHP-2) is a key node in the RAS signaling pathway. Allosteric inhibition of SHP2 phosphatase is a potential therapeutic strategy for cancers harboring oncogenic mutations in the KRAS pathway. SHP2 also participates in the signal transduction downstream of regulatory immunoreceptors, and it has been shown in preclinical models that SHP2 inhibition drives anti-tumor immunity through modulation of both innate and adaptive mechanism. BPI-442096 is a potent, selective, and orally bioavailable small molecule SHP2 inhibitor. It exhibited significant anti-proliferation activities against multiple KRAS mutant cancer cell lines, including those from NSCLC, PDAC, CRPC, etc. BPI-442096 dose-dependently inhibited SHP2 phosphatase and downstream ERK phosphorylation in cancer cells, as well as NFAT reporter gene expression downstream of PD-1/PD-L1 signaling in immune cells. In vivo, BPI-442096 demonstrated strong tumor growth inhibition in KRASG12C, KRASG12D, and KRASG12V mutant xenograft mouse models. BPI-442096 also exhibited anti-tumor immunity in the MC38 syngeneic model, as a single agent or in combination with anti-PD1/PD-L1 drugs. Moreover, BPI-442096 combining with KRASG12C inhibitor may reverse intrinsic and acquired resistance to KRASG12C inhibition. Adequate oral exposure across multiple pre-clinical species and good ADME properties ensured the druggability of BPI-442096. In conclusion, BPI-442096 exhibits a robust anti-tumor effect in multiple KRAS mutant models and enhanced anti-cancer immunity in syngeneic mouse models, and it shows multiple combination potentials to overcome drug resistance. Phase 1 clinical trial is planned in early 2022. Citation Format: Ling Li, Bang Fu, Han Han, Zhongxin Sun, Xiangdong Zhao, Xuepeng Jv, Jun Tong, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Wei Ren, Yinlong Li, Wenmao Wu, Jing Guo, Dan Yan, Xiangyong Liu, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5463.
Abstract 391: Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids
Authors: Kyrie Jean Pappas, Wouter Karthaus, Justin Laclair, Marco Russo, Charles Sawyers
Journal: Cancer Research (2022)

Abstract Cancers harboring bi-allelic loss of the breast cancer genes (BRCA1 and BRCA2) are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi), which are clinically approved in breast, ovarian, and more recently prostate cancer. Genetic alteration of BRCA2 is frequent in metastatic castration-resistant prostate cancer (mCRPC), and confers sensitivity to the PARPi olaparib; however, resistance is anticipated. mCRPC has a unique genetic landscape, and is likely to present different mechanisms of resistance compared to breast and ovarian cancer because loss of BRCA2 in prostate cancer occurs primarily through a large deletion of 13q that frequently includes Rb1; a setting in which reversion mutations of Brca2 are not possible. We have developed Brca2-deficient olaparib-sensitive murine prostate organoid models in clinically relevant genetic backgrounds (Brca2∆/∆Trp53∆/∆Pten∆/∆, Brca2∆/∆Trp53∆/∆, and Brca2∆/∆ sgRb1), as well as cell lines and patient-derived xenografts (PDX) to identify molecular mechanisms of olaparib resistance. We employed a genome-wide sgRNA positive selection screen to identify gene drivers of olaparib resistance in Brca2-deficient murine prostate organoid models. Putative resistance drivers are involved in many relevant pathways including DNA replication and repair, PARP1 substrate NAD+ metabolism, and androgen receptor signaling. While some pathways are genotype-specific, some are driving resistance in a pan-genotype manner. We are currently using our olaparib-sensitive model systems to validate specific resistance drivers in vitro and in vivo, determine their specificity to the BRCA1 or BRCA2 loss settings, and unravel the precise molecular mechanisms behind these resistance drivers. Citation Format: Kyrie Jean Pappas, Wouter Karthaus, Justin Laclair, Marco Russo, Charles Sawyers. Identifying molecular drivers of olaparib resistance through genome-wide sgRNA screening in prostate organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 391.